Identification of Candidate Gene Polymorphisms Associated with Infectious Diseas

宿主-病毒的相互作用受宿主基因和宿主蛋白的调节，宿主基因编码免疫反应元件，宿主蛋白是成功完成病原体生命周期所必需的。一种识别多态基因的候选基因方法正被用于识别在病毒感染发病机制中起作用的基因。这些基因座的识别为识别在病毒感染、复制、病毒组装和感染的免疫调节中起作用的宿主细胞成分提供了有价值的工具。明确宿主因素限制病毒疾病过程的机制将促进我们对病毒发病机制的理解，并可能导致可能的治疗干预。族裔/种族群体之间突变频率的差异也至少部分解释了艾滋病毒和乙型和丙型肝炎病毒(乙肝病毒和丙型肝炎病毒)的地理差异。我们正在研究宿主基因变异在疾病进展中的作用，在美国和中国的7,000多名参与者中登记了艾滋病毒、乙肝和丙型肝炎自然病史队列研究。我们的方法是：1)从研究参与者那里建立细胞系作为DNA的可再生来源；2)确定候选基因中的单核苷酸多态(SNPs)或插入/缺失(INDel)突变；3)使用高通量基因分型方法筛选SNPs；以及4)使用分类和生存分析来测试基因型和疾病表型之间的关联。编码HIV-1辅受体的配体RANTES基因启动子区域的多态与艾滋病进展的调节有关。单倍型分析表明，一个新的内含子变体要么跟踪功能位点，要么修改两个启动子变体的效果。在体外对5个与HIV-1结合的趋化因子受体编码基因的系统筛选中，我们在这些基因的功能区或编码区发现了6个SNPs。虽然这些标记物与HIV的发病机制无关，但它们可能是哮喘和关节炎等炎症性疾病的重要标记物。候选基因方法已经确定了至少10个影响艾滋病毒感染和病理的基因变异。虽然这些变异的影响很小，但它们加在一起约占艾滋病长期幸存者的30%-50%。我们使用HIV-1的基因分析作为复杂疾病的关联分析的模型，这些疾病既有遗传因素，也有环境因素，我们正在使用类似的策略来调查宿主基因对感染肝炎病毒、丙型肝炎病毒和乙肝病毒后预后的影响。这些重要的人类病毒感染具有全球性分布，在世界某些区域和某些风险群体中的流行率极高，并造成相当大的发病率和死亡率。它们还与患肝癌的风险增加有关，并具有相似的风险因素，尽管不是相同的。由于这些病毒的致病作用是高度可变的，不能完全用毒株差异或亚型来解释，暴露的不同结果有可能有遗传基础。我们目前正在收集患者进行病例对照研究，以确定影响病毒清除、进展为肝硬变和这些重要病原体对感染的抵抗力的候选基因。艾滋病和肝炎相关候选基因多态性的鉴定

Host-viral interactions are modulated by host genes encoding immune response elements and by host proteins required for the successful completion of the pathogen's lifecycle. A candidate gene approach to identify polymorphic loci is being used to identify genes that have a role in viral infection pathogenesis. Identification of such loci provides a valuable tool for the identification of host-cellular components that are operative in viral infection, replication, viral assembly, and immune regulation of the infection. Defining the mechanisms by which host factors restrict viral disease processes will advance our understanding of viral pathogenesis and may lead to possible therapeutic interventions. Differences in mutation frequencies between ethnic/racial groups may also explain at least in part the geographical variation observed for the HIV and hepatitis viruses B and C (HBV and HCV). We are investigating the role of host genetic variation on disease progression in over 7000 participants enrolled in HIV, HBV and HCV natural history cohort studies in the USA and China. Our approach has been to: 1) establish cell lines from study participants as a renewable source of DNA; 2) identify single nucleotide polymorphisms (SNPs) or insertion/deletion (indel) mutations in candidate genes; 3) screen SNPs using high throughput genotyping methods; and 4) use categorical and survival analyses to test for associations between genotypes and disease phenotypes.Polymorphisms in the promoter region of the gene encoding RANTES, a ligand for the HIV-1 coreceptor, are associated with modulation of AIDS progression. Haplotype analysis has revealed that a novel intron variant is either tracking the functional site or modifies the effect of two promoter variants. In a systematic screen of genes encoding 5 chemokine receptors that bind to HIV-1 in vitro, we have identified 6 SNPs in functional or coding regions of the genes. Although these markers are not associated with HIV pathogenesis, they may be important markers in inflammatory diseases such as asthma and arthritis. The candidate gene approach has led to the identification of at least ten genetic variants that affect HIV infection and pathology. Although the effect of each of these variants is small, together they account for approximately 30-50% of long-term AIDS survivors.Using the genetic analysis of HIV-1 as a model for association analysis of complex diseases which have both genetic and environmental components, we are employing a similar strategy to investigate the host genetic contributions to outcomes following infection with the hepatitis viruses, HCV and HBV. These important human viral infections have global distributions and extremely high prevalence rate in some regions of the world and among certain risk groups and cause considerable morbidity and mortality. They are also associated with increased risk of liver cancer, and have similar, although not identical, risk factors. Because pathogenic effects of these viruses are highly variable and not fully explained by strain differences or subtypes, it is plausable that differential outcomes to exposure have a genetic basis. We are currently accruing patients for case control studies to identify candidate genes which effect viral clearance, progression to cirrhosis, and resistance to infection for these important pathogens. Identification of Candidate Gene Polymorphisms Associated with AIDS and Hepatitis